Extended Treatment With PEG-Intron and Rebetol in Patients With Genotype 1 Chronic Hepatitis C and Slow Virologic Response (Study P03685AM3)

Condition(s) targeted: Hepatitis C, Chronic

Intervention: Combination of pegylated interferon alfa-2b and ribavirin (Drug); Combination of pegylated interferon alfa-2b and ribavirin (Drug)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: Schering-Plough

Official(s) and/or principal investigator(s):
Rafael Esteban, MD, Principal Investigator, Affiliation: Vall d'Hebron General Hospital

This is a controlled, randomized, parallel-groups, open-label, multinational study designed to evaluate the efficacy and safety of PEG-Intron plus Rebetol in subjects with chronic hepatitis C. It is designed to evaluate whether 72 weeks of treatment with PEG-Intron plus Rebetol is more effective than 48 weeks of treatment in subjects with Genotype 1 chronic hepatitis C who exhibit a slow response to treatment.

Official title: A Study to Assess Treatment With PEG-Intron® and Rebetol® in Naïve Patients With Genotype 1 Chronic Hepatitis C and Slow Virological Response

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Sustained virologic response, defined as a plasma HCV-RNA level below the lower level of quantitation (LLQ) at 24 weeks post-treatment.

Secondary outcome:

Early virological response at 12 weeks.

Virological response at end of treatment Weeks 48 and 72.

Evaluate the safety of 72 vs 48 weeks of treatment.

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Adult subjects aged 18 to 70 years, of either sex.

- Genotype-1 hepatitis C virus (HCV)-ribonucleic acid (RNA)-positive subjects.

- Subjects must be willing to give written informed consent and able to adhere to dosing

and visit schedules.

- Confirmation of liver biopsy availability: Availability of a liver biopsy performed

within 18 months prior to the Screen visit, with a pathology report confirming the histological diagnosis of chronic hepatitis or liver cirrhosis.

- Compensated liver disease with the following minimum hematological, biochemical, and

serological criteria at the screen visit (WNL = within normal limits, ULN = Upper Limit Normal):

- Hemoglobin values of equal or more than 12 g/dL for females and 13 g/dL for

males.

- White blood cells (WBCs) equal to or more than 3,000/mm^3

- Neutrophil count equal to or more than 1,500/mm^3

- Platelet count equal to or more than 80,000/mm^3

- Direct bilirubin up to 10% above ULN is acceptable.

- Indirect bilirubin up to 10% above ULN is acceptable (unless non-hepatitis

related factors such as Gilbert's disease explain an indirect bilirubin rise). In such cases indirect bilirubin should be less than or equal to 3. 0 mg/dL (less than or equal to 51. 3 µmol/L)

- Albumin up to 10% above ULN is acceptable.

- Serum creatinine up to 10% above ULN is acceptable.

- ALT level above ULN at Screen.

- At the Screen Visit, fasting glucose must be 70-140 mg/dL. Results between 116-140

mg/dL require repeat fasting glucose to be less than 140 mg/dL and HbA1C less than or equal to 8. 5%. HbA1C must be less than or equal to 8. 5% in diabetic subjects (whether on medication or diet controlled).

- Antinuclear antibodies (ANA) must be less than or equal to 1: 320.

- Thyroid Stimulating Hormone (TSH) WNL whether in euthyroid subjects or subjects

requiring medical treatment. (subjects requiring medication to maintain TSH levels within normal limits are eligible if all other inclusion/exclusion criteria are met).

- Confirmation by the principal investigator or a sub-investigator that sexually active

females of childbearing potential are practicing adequate contraception.

- Female subjects cannot be pregnant or breastfeeding and must be either postmenopausal,

surgically sterile or using 2 methods of birth control. While abstinence from sexual activity is the only certain method to prevent pregnancy, female patients of childbearing potential who are or who anticipate the possibility of becoming sexually active with a male partner must use a combination of the following 2 methods :

- Contraceptive pill or IUD or depot hormonal preparation (ring, injection implant)

and

- A barrier method of contraception such as diaphragm, sponge with spermicide,

condom, or a method of birth control considered acceptable by the study physician. Contraceptive measures will be reviewed with female subjects at each visit. Dual methods of contraception must be used for 1 month prior to the start of treatment and 6 months after treatment discontinuation.

- A serum pregnancy test obtained at Screen Visit prior to the initiation of treatment

must be negative.

- Confirmation by the principal investigator or a sub-investigator that sexually active

male subjects are practicing a method of contraception considered acceptable (vasectomy, condom plus spermicide, plus relationship with a female partner who practices an acceptable method of contraception). Contraception must be used during the treatment period and for seven months (or 6 months, according to local label) after the completion of therapy, including condom use by male subjects with pregnant partners.

- For subjects with a history of hypertension or diabetes, written clearance from an

ophthalmologist has to be obtained prior to treatment start.

Exclusion Criteria:

- Pregnant women, women who plan to become pregnant, male subjects whose partner wants

to become pregnant, and breastfeeding women.

- Previous treatment for chronic hepatitis C with an antiviral or immunomodulating agent

or with some interferon or ribavirin product, whether alone or in combination.

- Subjects weighing over 125 kg.

- Suspected hypersensitivity to any interferon or ribavirin product.

- Participation in other clinical trial within 30 days prior to screen into this study.

- Coinfection with HBV, HIV, or both.

- Any cause of liver disease other than chronic hepatitis C, including but not limited

to:

- Hemochromatosis

- Alpha-1 antitrypsin deficiency

- Wilson's disease

- Autoimmune hepatitis

- Alcoholic liver disease

- Non-alcoholic steatohepatitis (NASH)

- Drug-related liver disease

- Active malignant disease or suspicion or history of malignant disease within five

previous years (except for adequately treated basal cell carcinoma).

- Known coagulation diseases such as hemophilia; hemoglobin diseases (e. g.

thalassemia).

- Known glucose 6-phosphate dehydrogenase (G6PD) deficiency

- Evidence of advanced liver disease such as history or presence of ascites, bleeding

varices, or hepatic encephalopathy.

- Subjects with organ transplants, except for corneal or hair transplant.

- Any known preexisting medical condition that could interfere with the subject's

participation in and completion of study, such as:

- Preexisting psychiatric condition, especially moderate to severe depression, or a

history of severe psychiatric disorder, such as psychosis, suicidal ideation, or suicide attempts. Severe depression includes the following:

- Hospitalization for depression

- Electroconvulsive therapy for depression, or

- Depression causing a prolonged absence from work or significantly altering

daily functions.

- Subjects with mild depression may be considered for entry into the study provided

that a pre-treatment assessment demonstrates that the subject's emotional status is clinically stable, in which case a management plan must be formulated for the subject; this management plan will become a part of the subject's medical record.

- Craniocerebral trauma which is not a concussion, or active seizure disorders

requiring medication.

- Clinically significant ECG abnormalities and/or cardiovascular dysfunction within

6 previous months (e. g., angina, congestive heart failure, recent myocardial infarction, or significant arrhythmia).

- Chronic lung disease (e. g., chronic obstructive lung disease)

- Poorly controlled diabetes mellitus

- Immune-mediated disease (e. g., inflammatory bowel disease [Crohn's disease,

ulcerative colitis], idiopathic thrombocytopenic purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis)

- Clinical gout

- Subject is or was a substance abuser, such as alcohol (80 g/day or more), methadone,

IV, oral or inhaled drugs. To be considered for inclusion into the protocol, the subject must have abstained and agree to abstain from using any of the above for at least 6 months. Subjects treated with buprenorphine (Subutex) who have been stable for 6 months may be included.

- Cirrhotic subjects whose ultrasound confirms hepatocellular carcinoma.

- Any other condition that, in the investigator's opinion, could determine that

subject's participation in the study is not indicated or could interfere with the subject's participation in and completion of study.

- Subjacent disease that potentially would require systematic administration of

steroids

- Insulin dependent diabetes mellitus

Investigational Site 7, Vancouver V5Z 1H2, Canada

Investigational Site 8, Montreal H2X 1P1, Canada

Investigational Site 9, Montreal H3T 1E2, Canada

Investigational Site 10, Toronto M5G 1X5, Canada

Investigational Site 11, Winnipeg R3E 3P4, Canada

Investigational Site 12, Edmonton T6G 2B7, Canada

Investigational Site 14, Toronto M5G 2C4, Canada

Investigational Site 15, Vancouver V5Z 1M9, Canada

Investigational Site 16, London N6A 5A5, Canada

Investigational Site 1, Prague 4 14021, Czech Republic

Investigational Site 2, Brno 625 00, Czech Republic

Investigational Site 3, Prague 2 120 00, Czech Republic

Investigational Site 4, Plzen 304 60, Czech Republic

Investigational Site 47, Helsinki 00029 HUS, Finland

Investigational Site 35, Lyon Cedex 2 69288, France

Investigational Site 37, Creteil Cedex 94010, France

Investigational Site 38, Paris Cedex 13 75651, France

Investigational Site 39, Montpellier Cedex 5 34295, France

Investigational Site 40, Lille Cedex 59037, France

Investigational Site 41, Grenoble Cedex 38043, France

Investigational Site 42, Marseille Cedex 5 13385, France

Investigational Site 43, Saint Laurent du Var 06700, France

Investigational Site 44, Nice Cedex 06202, France

Investigational Site 45, Toulouse 31059, France

Investigational Site 46, Rennes Cedex 9 35033, France

Investigational Site 133, Marseille cedex 08 13285, France

Investigational Site 29, Heidelberg 69120, Germany

Investigational Site 24, Frankfurt am Main 60590, Germany

Investigational Site 28, Mannheim 68167, Germany

Investigational Site 32, Frankfurt, Germany

Investigational Site 26, Essen 45122, Germany

Investigational Site 112, Duesseldorf 40237, Germany

Investigational Site 17, Freiburg 79106, Germany

Investigational Site 18, Muenchen 81377, Germany

Investigational Site 31, Kiel 24105, Germany

Investigational Site 19, Berlin 13353, Germany

Investigational Site 20, Koeln 50937, Germany

Investigational Site 21, Rotenburg 27356, Germany

Investigational Site 25, Hamburg 20246, Germany

Investigational Site 30, Regensburg 93042, Germany

Investigational Site 22, Regensburg 93049, Germany

Investigational Site 23, Wuerzburg 97080, Germany

Investigational Site 63, Tel-Aviv 64239, Israel

Investigational Site 64, Zefat 13110, Israel

Investigational Site 65, Beer-Sheva 34101, Israel

Investigational Site 66, Jerusalem 91120, Israel

Investigational Site 114, Rechovot 76100, Israel

Investigational Site 131, Ramat Gan 52621, Israel

Investigational Site 54, Poznan 61-003, Poland

Investigational Site 55, Warszawa 01-201, Poland

Investigational Site 125, Bydgoszcz 85-0303, Poland

Investigational Site 126, Warszawa PL01-201, Poland

Investigational Site 127, Warszawa 02-507, Poland

Investigational Site 128, Wroclaw 51-149, Poland

Investigational Site 57, COIMBRA 3900, Portugal

Investigational Site 58, Porto 4369-004, Portugal

Investigational Site 56, Lisboa 1349-019, Portugal

Investigational Site 59, Moscow 125367, Russian Federation

Investigational Site 60, St.-Petersburg 190103, Russian Federation

Investigational Site 61, Smolensk 214001, Russian Federation

Investigational Site 62, Samara, Russian Federation

Investigational Site 78, Barcelona 08035, Spain

Investigational Site 88, Oviedo 33006, Spain

Investigational Site 79, Barcelona 08036, Spain

Investigational Site 85, Madrid 28035, Spain

Investigational Site 86, Santander 39008, Spain

Investigational Site 89, Madrid 28034, Spain

Investigational Site 90, Pamplona 31008, Spain

Investigational Site 92, La Coruna 15006, Spain

Investigational Site 93, Sevilla 41013, Spain

Investigational Site 94, Alicante, Spain

Investigational Site 95, Madrid 28006, Spain

Investigational Site 97, Burgos 09005, Spain

Investigational Site 67, Stockholm 17177, Sweden

Investigational Site 68, Stockholm 17177, Sweden

Investigational Site 75, Basel 4031, Switzerland

Investigational Site 129, Zuerich 8091, Switzerland

Investigational Site 130, Lausanne 1011, Switzerland

Investigational Site 76, Lugano 6900, Switzerland

Starting date: December 2004
Ending date: May 2008
Last updated: June 16, 2008